Ultrasonic imaging is among the most widely used abdominal imaging modalities in the United States. However, ultrasonic image quality is reported to be insuf?cient for diagnosis in up to 40% of patients, a challenge often correlated with obesity. The major problems are lack of penetration and reverberation clutter. We hypothesize that increasing the Mechanical Index (MI) from the current limit of 1.9 to values in the 2.4-3.4 range, with concomitant transmit pulse pressure increases from 40 to 200%, will markedly improve B-mode, har- monic, and Doppler image quality. We have designed this proposal to focus on harmonic imaging. Tissue harmonic imaging (THI) is a nonlinear method that is more robust to reverberation clutter and off-axis scattering than fundamental imaging, and has found great success in improving ultrasonic image quality. However, har- monic signal levels are 15-20 dB lower than fundamental signals, which leads to challenges with signal-to-noise ratio and depth penetration in dif?cult-to-image patients. The in situ pressures used in diagnostic ultrasound imaging have been subject to a de facto upper limit established by the United States FDA guidelines for the Mechanical Index (MI<1.9), a value which is based upon historic values, rather than being linked to scienti?c evidence of bioeffects. In tissues without gas bodies, cavitation based bioeffects have only been reported at diagnostic frequencies and pulse durations using MI values greater than 5.0. The American Institute of Ul- trasound in Medicine (AIUM) recently concluded that exceeding the recommended maximum MI given in the FDA guidance up to an estimated in situ value of 4.0, could be warranted without concern for increased risk of cavitation in non-fetal tissues without gas bodies, if imaging in this heretofore unexplored output regime were associated with a corresponding signi?cant clinical bene?t. We have obtained preliminary in vivo data using elevated MI harmonic imaging demonstrating +20 dB increases in harmonic signal level, penetration depth increases of up to 40%, and structural contrast-to-noise ratio increases from 12-500%, enabling visualization of additional structures. The primary goals of this work are to optimize elevated MI harmonic image quality and to quantify the resulting image quality improvements. There are 3 speci?c aims: 1) To extend our 3D nonlinear simulation tools to perform a parametric analysis of varying tissue properties and transducer con?gurations to optimize harmonic signal generation and image quality in elevated MI pulse inversion har- monic imaging, and to determine the relationship between water-based estimates and in situ measurements in the elevated MI output regime. 2) To design and implement a real-time prototype elevated MI system using commercial curvilinear abdominal arrays and a custom designed prototype large aperture low frequency diag- nostic array on a commercial grade scanner. 3) To quantify improvements in imaging performance afforded by the use of elevated MIs in patients scheduled for ultrasonic abdominal imaging studies, and in patients known to have malignant liver masses.